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Nano-Drugs Based on Nano Sterically Stabilized Liposomes for the Treatment of Inflammatory Neurodegenerative Diseases.

Turjeman K, Bavli Y, Kizelsztein P, Schilt Y, Allon N, Katzir TB, Sasson E, Raviv U, Ovadia H, Barenholz Y - PLoS ONE (2015)

Bottom Line: For the NSSL-MPS we also compared the effect of passive targeting alone and of active targeting based on short peptide fragments of ApoE or of β-amyloid.Our results clearly show that for NSSL-MPS, active targeting is not superior to passive targeting.The highly efficacious anti-inflammatory therapeutic feature of these two nano-drugs meets the criteria of disease-modifying drugs and supports further development and evaluation of these nano-drugs as potential therapeutic agents for diseases with an inflammatory component.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Membrane and Liposome Research, Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada (IMRIC), The Hebrew University-Hadassah Medical School, Jerusalem, Israel.

ABSTRACT
The present study shows the advantages of liposome-based nano-drugs as a novel strategy of delivering active pharmaceutical ingredients for treatment of neurodegenerative diseases that involve neuroinflammation. We used the most common animal model for multiple sclerosis (MS), mice experimental autoimmune encephalomyelitis (EAE). The main challenges to overcome are the drugs' unfavorable pharmacokinetics and biodistribution, which result in inadequate therapeutic efficacy and in drug toxicity (due to high and repeated dosage). We designed two different liposomal nano-drugs, i.e., nano sterically stabilized liposomes (NSSL), remote loaded with: (a) a "water-soluble" amphipathic weak acid glucocorticosteroid prodrug, methylprednisolone hemisuccinate (MPS) or (b) the amphipathic weak base nitroxide, Tempamine (TMN). For the NSSL-MPS we also compared the effect of passive targeting alone and of active targeting based on short peptide fragments of ApoE or of β-amyloid. Our results clearly show that for NSSL-MPS, active targeting is not superior to passive targeting. For the NSSL-MPS and the NSSL-TMN it was demonstrated that these nano-drugs ameliorate the clinical signs and the pathology of EAE. We have further investigated the MPS nano-drug's therapeutic efficacy and its mechanism of action in both the acute and the adoptive transfer EAE models, as well as optimizing the perfomance of the TMN nano-drug. The highly efficacious anti-inflammatory therapeutic feature of these two nano-drugs meets the criteria of disease-modifying drugs and supports further development and evaluation of these nano-drugs as potential therapeutic agents for diseases with an inflammatory component.

No MeSH data available.


Related in: MedlinePlus

Comparison of the therapeutic efficacy of NSSL-MPS and free MPS in the adoptive transfer EAE mice model.(A) SJL mice were treated by IV injections on days 8, 10, 12 post-T cell transfer with saline (control) (▲), free MPS (50mg/kg) (■) or NSSL-MPS (50mg/kg) (◆). (B) Treatment with NSSL-MPS reduced inflammation and demyelination in brains and spinal cords of mice with AT-EAE compared with free MPS treated mice and control mice. Brains and spinal cords were obtained on day 13 post T- cell transfer. Black arrows indicate infiltrating inflammatory cells; white arrow indicates demyelination. Representative H&E-stained brains (A,B,D,E,G) and spinal cord (C,F,H) sections from control (A-C), as well as NSSL-MPS (D-F) and free MPS treated EAE mice (G-H) show extensive inflammation involving perivascular infiltrates of mononuclear leukocytes (arrows) within the cerebral parenchyma and spinal cords of CTRL mice and free MPS treated mice (arrows). In the NSSL-MPS treated group, much fewer infiltrating cells were observed. LFB staining demonstrates extensive demyelination in the control spinal cord (J) and a decrease in myelin density in the free MPS treated group (I,L) around blood vessels compared with NSSL-MPS treated mice (K), demonstrating densely organized myelin sheaths. Original magnification of x 40.
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pone.0130442.g007: Comparison of the therapeutic efficacy of NSSL-MPS and free MPS in the adoptive transfer EAE mice model.(A) SJL mice were treated by IV injections on days 8, 10, 12 post-T cell transfer with saline (control) (▲), free MPS (50mg/kg) (■) or NSSL-MPS (50mg/kg) (◆). (B) Treatment with NSSL-MPS reduced inflammation and demyelination in brains and spinal cords of mice with AT-EAE compared with free MPS treated mice and control mice. Brains and spinal cords were obtained on day 13 post T- cell transfer. Black arrows indicate infiltrating inflammatory cells; white arrow indicates demyelination. Representative H&E-stained brains (A,B,D,E,G) and spinal cord (C,F,H) sections from control (A-C), as well as NSSL-MPS (D-F) and free MPS treated EAE mice (G-H) show extensive inflammation involving perivascular infiltrates of mononuclear leukocytes (arrows) within the cerebral parenchyma and spinal cords of CTRL mice and free MPS treated mice (arrows). In the NSSL-MPS treated group, much fewer infiltrating cells were observed. LFB staining demonstrates extensive demyelination in the control spinal cord (J) and a decrease in myelin density in the free MPS treated group (I,L) around blood vessels compared with NSSL-MPS treated mice (K), demonstrating densely organized myelin sheaths. Original magnification of x 40.

Mentions: As an alternative to direct induction with PLP, EAE can also be induced in SJL mice by adoptive transfer of in vitro neuroantigen-activated lymphocytes from mice immunized with these encephalitogenic neuroantigens. Induction of EAE by this method usually results in more severe disease, with higher incidence and a more accelerated and synchronous disease course. This model is a very sensitive therapeutic model of EAE, and was used extensively in MRI studies [47, 59]. We tested the therapeutic efficacy of our NSSL-MPS formulation compared to the free MPS drug under stringent conditions, starting treatment at the time of first clinical signs of EAE (Fig 7A, Table 7). We compared the therapeutic effect of NSSL-MPS and the free MPS drug. Mice were injected on days 8, 9, and 10 after T-cell transfer with the onset of clinical signs. For both treatment groups, the liposomal and the free MPS, the mean maximal score disease duration and the mean burden of disease were significantly improved compared to control group. Although treatment with free MPS showed clear efficacy, treatment with the liposomal MPS was much more effective. At day 13 after T-cell transfer, we examined the brains and spinal cords of mice from each treatment group (CTRL, free MPS, and NSSL-MPS) using luxol fast blue (LFB) and hematoxylin and eosin (H&E) staining as indications of demyelination and leukocyte infiltration, respectively, to determine whether the differences in therapeutic efficacy correspond to differences in neuropathology (Fig 7B). H&E staining clearly showed inflammation and accumulation of infiltrated cells in the brain and spinal cord. In both the control group (sham-treated) and the free MPS-treated group, cellular infiltrates were dense in the parenchyma and perivascular spaces, brainstem, cortex, and cerebellum.


Nano-Drugs Based on Nano Sterically Stabilized Liposomes for the Treatment of Inflammatory Neurodegenerative Diseases.

Turjeman K, Bavli Y, Kizelsztein P, Schilt Y, Allon N, Katzir TB, Sasson E, Raviv U, Ovadia H, Barenholz Y - PLoS ONE (2015)

Comparison of the therapeutic efficacy of NSSL-MPS and free MPS in the adoptive transfer EAE mice model.(A) SJL mice were treated by IV injections on days 8, 10, 12 post-T cell transfer with saline (control) (▲), free MPS (50mg/kg) (■) or NSSL-MPS (50mg/kg) (◆). (B) Treatment with NSSL-MPS reduced inflammation and demyelination in brains and spinal cords of mice with AT-EAE compared with free MPS treated mice and control mice. Brains and spinal cords were obtained on day 13 post T- cell transfer. Black arrows indicate infiltrating inflammatory cells; white arrow indicates demyelination. Representative H&E-stained brains (A,B,D,E,G) and spinal cord (C,F,H) sections from control (A-C), as well as NSSL-MPS (D-F) and free MPS treated EAE mice (G-H) show extensive inflammation involving perivascular infiltrates of mononuclear leukocytes (arrows) within the cerebral parenchyma and spinal cords of CTRL mice and free MPS treated mice (arrows). In the NSSL-MPS treated group, much fewer infiltrating cells were observed. LFB staining demonstrates extensive demyelination in the control spinal cord (J) and a decrease in myelin density in the free MPS treated group (I,L) around blood vessels compared with NSSL-MPS treated mice (K), demonstrating densely organized myelin sheaths. Original magnification of x 40.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4492950&req=5

pone.0130442.g007: Comparison of the therapeutic efficacy of NSSL-MPS and free MPS in the adoptive transfer EAE mice model.(A) SJL mice were treated by IV injections on days 8, 10, 12 post-T cell transfer with saline (control) (▲), free MPS (50mg/kg) (■) or NSSL-MPS (50mg/kg) (◆). (B) Treatment with NSSL-MPS reduced inflammation and demyelination in brains and spinal cords of mice with AT-EAE compared with free MPS treated mice and control mice. Brains and spinal cords were obtained on day 13 post T- cell transfer. Black arrows indicate infiltrating inflammatory cells; white arrow indicates demyelination. Representative H&E-stained brains (A,B,D,E,G) and spinal cord (C,F,H) sections from control (A-C), as well as NSSL-MPS (D-F) and free MPS treated EAE mice (G-H) show extensive inflammation involving perivascular infiltrates of mononuclear leukocytes (arrows) within the cerebral parenchyma and spinal cords of CTRL mice and free MPS treated mice (arrows). In the NSSL-MPS treated group, much fewer infiltrating cells were observed. LFB staining demonstrates extensive demyelination in the control spinal cord (J) and a decrease in myelin density in the free MPS treated group (I,L) around blood vessels compared with NSSL-MPS treated mice (K), demonstrating densely organized myelin sheaths. Original magnification of x 40.
Mentions: As an alternative to direct induction with PLP, EAE can also be induced in SJL mice by adoptive transfer of in vitro neuroantigen-activated lymphocytes from mice immunized with these encephalitogenic neuroantigens. Induction of EAE by this method usually results in more severe disease, with higher incidence and a more accelerated and synchronous disease course. This model is a very sensitive therapeutic model of EAE, and was used extensively in MRI studies [47, 59]. We tested the therapeutic efficacy of our NSSL-MPS formulation compared to the free MPS drug under stringent conditions, starting treatment at the time of first clinical signs of EAE (Fig 7A, Table 7). We compared the therapeutic effect of NSSL-MPS and the free MPS drug. Mice were injected on days 8, 9, and 10 after T-cell transfer with the onset of clinical signs. For both treatment groups, the liposomal and the free MPS, the mean maximal score disease duration and the mean burden of disease were significantly improved compared to control group. Although treatment with free MPS showed clear efficacy, treatment with the liposomal MPS was much more effective. At day 13 after T-cell transfer, we examined the brains and spinal cords of mice from each treatment group (CTRL, free MPS, and NSSL-MPS) using luxol fast blue (LFB) and hematoxylin and eosin (H&E) staining as indications of demyelination and leukocyte infiltration, respectively, to determine whether the differences in therapeutic efficacy correspond to differences in neuropathology (Fig 7B). H&E staining clearly showed inflammation and accumulation of infiltrated cells in the brain and spinal cord. In both the control group (sham-treated) and the free MPS-treated group, cellular infiltrates were dense in the parenchyma and perivascular spaces, brainstem, cortex, and cerebellum.

Bottom Line: For the NSSL-MPS we also compared the effect of passive targeting alone and of active targeting based on short peptide fragments of ApoE or of β-amyloid.Our results clearly show that for NSSL-MPS, active targeting is not superior to passive targeting.The highly efficacious anti-inflammatory therapeutic feature of these two nano-drugs meets the criteria of disease-modifying drugs and supports further development and evaluation of these nano-drugs as potential therapeutic agents for diseases with an inflammatory component.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Membrane and Liposome Research, Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada (IMRIC), The Hebrew University-Hadassah Medical School, Jerusalem, Israel.

ABSTRACT
The present study shows the advantages of liposome-based nano-drugs as a novel strategy of delivering active pharmaceutical ingredients for treatment of neurodegenerative diseases that involve neuroinflammation. We used the most common animal model for multiple sclerosis (MS), mice experimental autoimmune encephalomyelitis (EAE). The main challenges to overcome are the drugs' unfavorable pharmacokinetics and biodistribution, which result in inadequate therapeutic efficacy and in drug toxicity (due to high and repeated dosage). We designed two different liposomal nano-drugs, i.e., nano sterically stabilized liposomes (NSSL), remote loaded with: (a) a "water-soluble" amphipathic weak acid glucocorticosteroid prodrug, methylprednisolone hemisuccinate (MPS) or (b) the amphipathic weak base nitroxide, Tempamine (TMN). For the NSSL-MPS we also compared the effect of passive targeting alone and of active targeting based on short peptide fragments of ApoE or of β-amyloid. Our results clearly show that for NSSL-MPS, active targeting is not superior to passive targeting. For the NSSL-MPS and the NSSL-TMN it was demonstrated that these nano-drugs ameliorate the clinical signs and the pathology of EAE. We have further investigated the MPS nano-drug's therapeutic efficacy and its mechanism of action in both the acute and the adoptive transfer EAE models, as well as optimizing the perfomance of the TMN nano-drug. The highly efficacious anti-inflammatory therapeutic feature of these two nano-drugs meets the criteria of disease-modifying drugs and supports further development and evaluation of these nano-drugs as potential therapeutic agents for diseases with an inflammatory component.

No MeSH data available.


Related in: MedlinePlus